Background and Rationale
The Wilms' tumor gene, WT1, was first identified in childhood renal tumors, but WT1 is also highly expressed in multiple other hematologic malignancies and solid tumors and, in particular, mesothelioma. WT1 is normally expressed in tissues of the mesodermal origin during embryogenesis including the kidney, gonads, heart, mesothelium, and spleen. In normal adult tissues, WT1 expression is limited to low levels in the nuclei of normal CD34+ hematopoietic stem cells, myoepithelial progenitor cells, renal podocytes, and some cells in the testis and ovary.
The strong expression of WT-1 protein in mesothelioma and myeloid and lymphoid neoplasms makes these cancers rational targets for first therapeutic attempts. In AML, WT1 expression can be used to monitor disease progression or relapse. One investigator reported that WT1 transcript numbers paralleled other molecular markers used for minimal residual disease monitoring. In a series of patients monitored prospectively, increased WT1 expression always indicated impending hematologic relapse even in patients lacking other molecular markers. Normal WT1 transcript copy numbers in treated leukemia patients were associated with persisting complete remission.
The use of WT1-derived peptides for vaccination of AML and certain carcinomas has also been reported in Japan and Germany. Clinical responses have been seen in small groups of patients. The NIH is also conducting a trial with the native WT1 A0201 peptide mixed with another myeloid antigen peptide (PR1) in patients with AML. After vaccination, the emergence of PR1 or WT1(+) CD8(+) T cells was associated with a decrease in WT1 mRNA expression as a marker of minimal residual disease, suggesting a vaccine-driven antileukemia effect.
At Memorial Sloan-Kettering, we conducted a pilot trial in AML and mesothelioma to determine the immunogenicity and safety of vaccination with our WT1 heteroclitic peptides in humans (IRB# 06-085). As described above, in order to broaden the immune response in the setting of varied HLA subtypes, four different peptides were included in the vaccine. Peptides were suspended in Montanide adjuvant, and GM-CSF was administered at the injection site. Patients were required to have neoplasms that showed immunohistochemical staining for WT1 in greater than 10 percent of cells. All HLA subtypes were eligible. The vaccine was well tolerated except for one patient with a grade 2 allergic reaction, who was removed from study.
We evaluated nine AML patients in remission and expected to receive no additional therapy. Seven of the eight tested patients responded with CD4 responses to the long peptides and three of the three HLA-A0201 patients responded to the class 1 peptide. Median overall survival was approximately 35 months for the group as a whole. The median disease-free survival was not reached for this small group of patients. Although only a small number of patients were treated, the results are intriguing enough to warrant further study in a larger clinical trial examining the role of vaccination as a viable treatment for AML and ALL. This is the rationale for the current study.
Key Eligibility Criteria
- Morphologic confirmation of a diagnosis of AML or ALL at Memorial Sloan-Kettering
- Patients will have completed induction therapy, achieved first complete remission (CR), and completed any planned postremission therapy. Patients are not candidates for allogeneic stem cell transplantation. For purposes of this study, patients who are not candidates for allogeneic stem cell transplantation shall be defined as 1) those who do not meet the eligibility criteria of an open allogeneic transplant protocol or 2) those who do not have a suitable available HLA-matched donor available or 3) those who refuse to undergo stem cell transplantation or 4) those whose disease is characterized by “good risk” features — for AML the following cytogenetic subtypes: t(8;21), inv (16) or t(16;16), t(15;17), and normal karyotype with mutated NPM1 and negative for tandem duplication of FLT-3; for ALL: T cell phenotype or any B lineage disease exclusive of t(9;22) or t(4;11) — in whom allogeneic stem cell transplantation in first CR would not be offered as standard of care.
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- Alternatively, those patients ≥ 60 years of age who have achieved first CR and in whom no further postremission chemotherapy is planned may be enrolled.
- Patients must have documented WT1+ disease. For purposes of this study, this is defined as the detectable presence of any WT1 transcript via RT-PCR on a bone marrow study performed at Memorial Sloan-Kettering within four weeks prior to the administration of the first dose of vaccine.
- Patients must be within two years of achieving CR following chemotherapy.
- At least four weeks must have elapsed between the patient's last chemotherapy or radiation treatment and the first vaccination.
- Age > 18 years
- Karnofsky performance status > 50%
- Hematologic parameters:
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- Absolute neutrophil count (ANC) > 1000/μl
- Platelets > 50k/ μl
- Biochemical parameters:
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- Total bilirubin < 2.0 mg/dl
- AST and ALT < 2.5 x upper limits of normal
- Creatinine < 2.0 mg/dl
Study Objectves
Primary Objective
To assess the safety and efficacy of the WT1 peptide vaccine administered to patients in complete remission from AML or ALL. Any toxicity noted in the trial will be graded in accordance with Common Toxicity Criteria, version 4.0 (CTCAE 4.0) developed by the National Cancer Institute, June 10, 2003. For purposes of this study, the primary efficacy measure is defined as overall survival at three years.
Secondary Objectives
- Disease-free survival
- To assess the immunologic responses of vaccine administration via CD4+ T cell proliferation, CD3+ T cell interferon- γ release (ELISPOT and / or flow cytometry), and WT1 peptide tetramer staining.
- To assess any effect on minimal residual disease as measured by RT-PCR for WT1 transcript.
Study Design
This is a phase II study evaluating the safety and efficacy of the WT1 peptide vaccine in patients who are in complete remission from AML/ALL. Twenty- nine patients with a history of AML or ALL who have completed all planned chemotherapy will be enrolled in this study. Patients will be vaccinated with a preparation of WT1-derived native and synthetic peptides plus the immunologic adjuvant Montanide ISA 51 VG (Seppic Pharmaceuticals, Fairfield, NJ) and Sargarmostim (GM-CSF; Bayer Healthcare Pharmaceuticals, Seattle, WA).
Patients will receive six vaccinations over ten weeks. Early toxicity will be assessed at weeks two and four. Routine toxicity assessments will continue throughout the trial. Immune responses will be evaluated at week 12 via CD4+ T cell proliferation, CD3+ T cell interferon- γ interferon release (ELISPOT and / or flow cytometry), and WT1 peptide tetramer staining. Potential effects on minimal residual disease (MRD) will be assessed via RT-PCR for WT1 transcript in bone marrow aspirates from the same time-point. Patients who are clinically stable and have not had disease recurrence may continue with up to six more vaccinations administered approximately every month. In that case, patients will be reevaluated with bone marrow and immunologic studies after the completion of all vaccinations.
Contact
For more information and to see if your patient is eligible for this study, please contact Dr. Peter Maslak at 212-639-5518.
